The host RNA polymerase II C-terminal domain is the anchor for replication of the influenza virus genome

Nat Commun. 2024 Feb 5;15(1):1064. doi: 10.1038/s41467-024-45205-2.

Abstract

The current model is that the influenza virus polymerase (FluPol) binds either to host RNA polymerase II (RNAP II) or to the acidic nuclear phosphoprotein 32 (ANP32), which drives its conformation and activity towards transcription or replication of the viral genome, respectively. Here, we provide evidence that the FluPol-RNAP II binding interface, beyond its well-acknowledged function in cap-snatching during transcription initiation, has also a pivotal role in replication of the viral genome. Using a combination of cell-based and in vitro approaches, we show that the RNAP II C-terminal-domain, jointly with ANP32, enhances FluPol replication activity. We observe successive conformational changes to switch from a transcriptase to a replicase conformation in the presence of the bound RNPAII C-terminal domain and propose a model in which the host RNAP II is the anchor for transcription and replication of the viral genome. Our data open new perspectives on the spatial coupling of viral transcription and replication and the coordinated balance between these two activities.

MeSH terms

  • DNA-Directed RNA Polymerases
  • Orthomyxoviridae* / genetics
  • RNA Polymerase II* / metabolism
  • RNA, Viral / genetics
  • RNA-Dependent RNA Polymerase / metabolism
  • Virus Replication / genetics

Substances

  • RNA Polymerase II
  • RNA-Dependent RNA Polymerase
  • RNA, Viral
  • DNA-Directed RNA Polymerases